This research will continue to characterize the process of oral immunization, one of the ways newborn mammals become immunized against environmental antigens. Since immunization of the newborn frequently occurs in the presence of placentally transferred antibody which may enter the gastrointestinal tract, the effect of passive immunity on the humoral and cellular immune responses to orally administered protein antigen will be determined. The systemic immune response following oral immunization may occur by the movement of sensitized lymphoid cells or the absorption of sufficient antigen to immunize the systemic lymphoid tissue. To distinguish between these two mechanisms the concentration of ingested antigen will be increased 60 fold and the route of antigen absorption and location of the sensitization to the antigen will be studied. The lymphocytes of the gut-associated lymphoid tissues will be examined as the probable site of both local and circulating antibody production. The principles of oral immunization will be adapted to the oral administration of diphtheria toxin. If animal experiments are successful and show that this method is safe, these findings will be used to develop a model system for human disease prophylaxis by the use of formula additives. Antisera from normal and milk intolerant infants will be compared to learn if internal determinants exposed by digestion are recognized by either group. The failure of orally immunized adult rabbits to recognize internal determinants appears to be related to the variable action of pepsin. The difference between normal and intolerant infants may be that intolerant infants digest the antigen more uniformly resulting in immunization to new determinants. The antibodies and circulating antigen reactive cells against purified milk proteins present in both groups of infants will be compared. The long term goals are to characterize the normal immunologic responses of the newborn, identify deviations from the normal which may be associated with disease, and provide a more acceptable, more widely applicable method for the immunization of newborns against bacterial toxins.